Chikungunya virus (CHIKV), is an emerging, mosquito-borne alphavirus and potential biological weapon that has caused debilitating, chronic arthralgia in at least 2 million persons in Asia and Africa since 2005. CHIKV was recently placed on the NIAID list of priority pathogens as a recognition of it's emergence potential. Due to difficulties with clinical diagnosis, it is grossly underreported and probably causes far more disease than is recognized, including fatalities. Like dengue virus, CHIKV uses humans as amplifying hosts and therefore can disseminate readily in travelers, suggesting that it will eventually become established the Americas. A 2007 epidemic in Italy underscores the threat of CHIKV to developed nations like the U.S., including temperate regions populated by the efficient vector, Aedes albopictus. There are no licensed vaccines or therapies for CHIKV, and the only IND vaccine strain tested in humans is reactogenic. We will capitalize on our chimeric alphavirus technology to develop novel CHIKV vaccines that are superior to traditional, cell culture-adapted mutants. Using genetic backbones derived from relatively avirulent alphaviruses and structural protein genes from CHIKV, we will optimize vaccine candidates that replicate efficiently in Vero cells, and are highly attenuated yet rapidly immunogenic and efficacious in preventing viremia and disease. Further attenuation will be achieved by introducing mutations from the previously evaluated IND CHIKV vaccine strain, and by inactivating the CHIKV virulence mechanism of host cell gene expression shutoff. Mosquito transmissibility will also be eliminated using novel genetic approaches. Optimized vaccines will be evaluated in mice for safety, immunogenicity and efficacy. Following mosquito transmissibility assessment and evaluation of stability, the 2 leading vaccine candidates will be ready for evaluation in prmates and for the final stages of product development. The resulting vaccine will dramatically improve U.S. preparedness for CHIKV introduction, minimize the risk of importation by reducing transmission in endemic locations, and provide the first effective prevention for an important disease of many developing nations. In addition, further development of our chimeric vaccine platform technology will allow us to rapidly generate vaccines against other alphaviruses that emerge in the future. 1